基于网络药理学和生物信息学的辛伐他汀分子生物学机制研究
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摘要
目的通过生物信息学分析研究辛伐他汀作用前后的差异表达基因,找出参与辛伐他汀体内作用的关键基因,并对其所涉及的功能进行分析预测。方法从美国国立生物技术信息中心公共基因芯片数据平台下载辛伐他汀对人外周血单核细胞-巨噬细胞基因表达谱影响的mRNA基因芯片数据集GSE4883,包含辛伐他汀给药组6个样本及对照组3个样本,用R语言Limma函数包筛选差异表达的mRNA,并用Benjamini&Hochberg错误发现率对原始P值进行多重矫正,并进一步用DAVID数据库对靶基因进行基因本体论(GO)和京都基因与基因组百科全书(KEGG)信号通路富集分析,之后用STRING数据库构建蛋白质相互作用网络,同时用Cytoscape对模块中的基因共表达关系进行可视化,筛选关键基因。结果共筛选出214个辛伐他汀作用前后差异表达的基因。GO分析显示,差异表达基因生物学功能主要涉及免疫反应、细胞对白细胞介素-1、干扰素的反应和单核细胞趋化性。KEGG分析显示,差异表达基因主要和细胞因子与细胞因子受体相互作用、类风湿关节炎和趋化因子信号通路等有关。蛋白质相互作用网络筛选出KIF11、CDK1、NDC80、RRM2、NCAPG、NUF2、MAD2L1、KIF15、TOP2A和HELLS 10个关键基因。结论生物信息学能有效筛选和分析辛伐他汀作用后的相关差异表达基因,通过对辛伐他汀作用后的表达谱进行分析,为进一步探讨辛伐他汀作用的分子机制及靶点提供思路,同时为他汀类药物的潜在应用探索提供理论依据。
Objective To analyze the molecular biological mechanism of simvastatin in the treatment of human based on network pharmacology and bioinformatics methods. Methods The human mRNA gene chip dataset GSE4883( 6 samples of simvastatin group and 3 samples of control group) was downloaded from common gene chip data platform in National Center for Biotechnology Information. Differentially expressed mRNAs was screened by using Limma package based on Benjamini & Hochberg false discovery rate algorithm of R language. Gene ontologies( GOs) and Kyoto Encyclopedia of Genes and Genomes( KEGG) signal pathway enrichment analysis were performed by using DAVID database. The protein-protein interaction network was constructed by STRING-db database,and hub genes were obtained by Cytoscape. Results The differential expression of mRNA gene chip data set GSE4883 showed that 214 mRNAs were differentially expressed. GO analysis indicated that several functional pathways,such as immune response,cellular response to interleukin-1,interferon and monocyte chemotaxis were enriched. KEGG pathway analysis showed some related pathways,including cytokine-cytokine receptor interaction,rheumatoid arthritis andchemokine signaling pathways. Ten hub genes were obtained from the protein-protein interaction network,including KIF11,CDK1,NDC80,RRM2,NCAPG,NUF2,MAD2L1,KIF15,TOP2A and HELLS. Conclusion Bioinformatic methods for screening simvastatin related DEGs can provide a new way for new biomarkers of simvastatin treatment. The genes identified in the present study might be prognostic factors as well as potential therapeutic targets in the usage of simvastatin.
Objective To analyze the molecular biological mechanism of simvastatin in the treatment of human based on network pharmacology and bioinformatics methods. Methods The human mRNA gene chip dataset GSE4883( 6 samples of simvastatin group and 3 samples of control group) was downloaded from common gene chip data platform in National Center for Biotechnology Information. Differentially expressed mRNAs was screened by using Limma package based on Benjamini & Hochberg false discovery rate algorithm of R language. Gene ontologies( GOs) and Kyoto Encyclopedia of Genes and Genomes( KEGG) signal pathway enrichment analysis were performed by using DAVID database. The protein-protein interaction network was constructed by STRING-db database,and hub genes were obtained by Cytoscape. Results The differential expression of mRNA gene chip data set GSE4883 showed that 214 mRNAs were differentially expressed. GO analysis indicated that several functional pathways,such as immune response,cellular response to interleukin-1,interferon and monocyte chemotaxis were enriched. KEGG pathway analysis showed some related pathways,including cytokine-cytokine receptor interaction,rheumatoid arthritis andchemokine signaling pathways. Ten hub genes were obtained from the protein-protein interaction network,including KIF11,CDK1,NDC80,RRM2,NCAPG,NUF2,MAD2L1,KIF15,TOP2A and HELLS. Conclusion Bioinformatic methods for screening simvastatin related DEGs can provide a new way for new biomarkers of simvastatin treatment. The genes identified in the present study might be prognostic factors as well as potential therapeutic targets in the usage of simvastatin.
引文
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[3]黄凌凌,吴赟,魏斌.辛伐他汀通过调节转化生长因子β1/Smad 3通路抑制牙槽骨成骨细胞凋亡的机制研究[J].中国临床药理学杂志,2019,35(7):671-673,677.
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[6]赵庆霞,张秀梅,纪征,等.辛伐他汀联合通脉颗粒治疗不稳定型心绞痛的临床疗效及安全性评价[J].中国临床药理学杂志,2016,32(8):690-692.
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[9] DAIGO K,TAKANO A,THANG P M,et al. Characterization of KIF11 as a novel prognostic biomarker and therapeutic target for oral cancer[J]. Int J Oncol,2018,52(1):155-165.
[10] AHERN T P,LASH T L,DAMKIER P,et al. Statins and breast cancer prognosis:evidence and opportunities[J/OL]. Lancet Oncol, 2014,15(10):E461-E468. 2014-09-30[2019-05-10]. https://linkinghub. elsevier. com/retrieve/pii/S1470-2045(14)70119-6.
[11] NIELSEN S F,NORDESTGAARD B G,BOJESEN S E. Statin use and reduced cancer-related mortality[J]. New Engl J Med,2012,367(19):1792-1802.
[12] ASGHAR U,WITKIEWICZ A K,TURNER N C,et al. The history and future of targeting cyclin-dependent kinases in cancer therapy[J]. Nat Rev Drug Discov,2015,14(2):130-146.
[13] TSAI W C,YU T Y,LIN L P,et al. Prevention of simvastatininduced inhibition of tendon cell proliferation and cell cycle progression by geranylgeranyl pyrophosphate[J]. Toxicol Sci,2016,149(2):326-334.
[14] KANY S,WOSCHEK M,KNEIP N,et al. Simvastatin exerts anticancer effects in osteosarcoma cell lines via geranylgeranylation and c-Jun activation[J]. Int J Oncol,2018,52(4):1285-1294.
[2]赵丹生,马晓峰.辛伐他汀联合银杏叶片对心性猝死综合征患者的血脂及颈动脉粥样硬化斑块的影响[J].中国临床药理学杂志,2017,33(13):1171-1173.
[3]黄凌凌,吴赟,魏斌.辛伐他汀通过调节转化生长因子β1/Smad 3通路抑制牙槽骨成骨细胞凋亡的机制研究[J].中国临床药理学杂志,2019,35(7):671-673,677.
[4] ELMASRY A,ALADEEB N M,ELKAREF A,et al. Simvastatin exerts antifibrotic effect and potentiates the antischistosomal effects of praziquantel in a murine model:Role of IL10[J/OL]. Biomed Pharmacother, 2017,96:215-221. 2017-12-31[2019-05-01]. https://www. sciencedirect. com/science/article/abs/pii/S0753332217326951.
[5]孙春玲,洪华山,江琼.辛伐他汀对急性心肌梗死大鼠微血管新生的影响[J].中国临床药理学杂志,2008,24(5):430-434.
[6]赵庆霞,张秀梅,纪征,等.辛伐他汀联合通脉颗粒治疗不稳定型心绞痛的临床疗效及安全性评价[J].中国临床药理学杂志,2016,32(8):690-692.
[7] JIANG M,ZHUANG H,XIA R,et al. KIF11 is required for proliferation and self-renewal of docetaxel resistant triple negative breast cancer cells[J]. Oncotarget,2017,8(54):92106-92118.
[8] ASBAGHI Y,THOMPSON L L,LICHTENSZTEJN Z,et al. KIF11silencing and inhibition induces chromosome instability that may contribute to cancer[J]. Genes Chromosomes Cancer,2017,56(9):668-680.
[9] DAIGO K,TAKANO A,THANG P M,et al. Characterization of KIF11 as a novel prognostic biomarker and therapeutic target for oral cancer[J]. Int J Oncol,2018,52(1):155-165.
[10] AHERN T P,LASH T L,DAMKIER P,et al. Statins and breast cancer prognosis:evidence and opportunities[J/OL]. Lancet Oncol, 2014,15(10):E461-E468. 2014-09-30[2019-05-10]. https://linkinghub. elsevier. com/retrieve/pii/S1470-2045(14)70119-6.
[11] NIELSEN S F,NORDESTGAARD B G,BOJESEN S E. Statin use and reduced cancer-related mortality[J]. New Engl J Med,2012,367(19):1792-1802.
[12] ASGHAR U,WITKIEWICZ A K,TURNER N C,et al. The history and future of targeting cyclin-dependent kinases in cancer therapy[J]. Nat Rev Drug Discov,2015,14(2):130-146.
[13] TSAI W C,YU T Y,LIN L P,et al. Prevention of simvastatininduced inhibition of tendon cell proliferation and cell cycle progression by geranylgeranyl pyrophosphate[J]. Toxicol Sci,2016,149(2):326-334.
[14] KANY S,WOSCHEK M,KNEIP N,et al. Simvastatin exerts anticancer effects in osteosarcoma cell lines via geranylgeranylation and c-Jun activation[J]. Int J Oncol,2018,52(4):1285-1294.